U.S. patent application number 13/984170 was filed with the patent office on 2013-11-28 for tissue adhesive based on trifunctional aspartates.
This patent application is currently assigned to Bayer Intellectual Property GmbH Creative Campus Monheim. The applicant listed for this patent is Christoph Eggert, Heike Heckroth. Invention is credited to Christoph Eggert, Heike Heckroth.
Application Number | 20130317134 13/984170 |
Document ID | / |
Family ID | 44276278 |
Filed Date | 2013-11-28 |
United States Patent
Application |
20130317134 |
Kind Code |
A1 |
Heckroth; Heike ; et
al. |
November 28, 2013 |
TISSUE ADHESIVE BASED ON TRIFUNCTIONAL ASPARTATES
Abstract
The present invention relates to a compound of formula (I)
wherein R.sub.1, R.sub.2 each independently of the other are
identical or different organic radicals which do not contain
Zerewitinoff-active hydrogen, and R.sub.4, R.sub.5, R.sub.6 each
independently of the others are saturated, linear or branched
organic radicals which do not contain Zerewitinoff-active hydrogen
and which are also optionally substituted in the chain by
heteroatoms, for use in a polyurea system which is provided in
particular for sealing, bonding, gluing or covering cell tissue.
The invention further provides a polyurea system comprising the
compound according to the invention, and a metering system for the
polyurea system according to the invention. ##STR00001##
Inventors: |
Heckroth; Heike; (Odenthal,
DE) ; Eggert; Christoph; (Koln, DE) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Heckroth; Heike
Eggert; Christoph |
Odenthal
Koln |
|
DE
DE |
|
|
Assignee: |
Bayer Intellectual Property GmbH
Creative Campus Monheim
Monheim
DE
|
Family ID: |
44276278 |
Appl. No.: |
13/984170 |
Filed: |
February 6, 2012 |
PCT Filed: |
February 6, 2012 |
PCT NO: |
PCT/EP2012/051934 |
371 Date: |
August 7, 2013 |
Current U.S.
Class: |
523/118 ;
137/602; 560/169 |
Current CPC
Class: |
C08G 18/10 20130101;
A61L 24/046 20130101; Y10T 137/87571 20150401; C08G 18/3821
20130101; C08L 75/02 20130101; A61L 24/046 20130101; C08G 18/3821
20130101; C08G 18/10 20130101 |
Class at
Publication: |
523/118 ;
560/169; 137/602 |
International
Class: |
A61L 24/04 20060101
A61L024/04 |
Foreign Application Data
Date |
Code |
Application Number |
Feb 9, 2011 |
EP |
11153807.0 |
Claims
1-16. (canceled)
17. A compound of formula (I) ##STR00008## wherein R.sub.1 and
R.sub.2 each independently of the other are identical or different
organic radicals which do not contain Zerewitinoff-active hydrogen,
and R.sub.4, R.sub.5 and R.sub.6 each independently of the others
are saturated, linear or branched organic radicals which do not
contain Zerewitinoff-active hydrogen and which are also optionally
substituted in the chain by heteroatoms.
18. The compound according to claim 17, wherein the radicals
R.sub.4, R.sub.5 and R.sub.6 each independently of the others are
linear or branched, saturated, aliphatic C1 to C12 hydrocarbon
radicals.
19. The compound according to claim 17, wherein the radicals
R.sub.4, R.sub.5 and R.sub.6 each independently of the others are
saturated, aliphatic C3 to C6 hydrocarbon radicals.
20. The compound according to claim 17, wherein the radicals
R.sub.1 and R.sub.2 each independently of the other are linear or
branched organic C1 to C10.
21. The compound according to claim 17, wherein the radicals
R.sub.1 and R.sub.2 each independently of the other are linear or
branched C2 to C4 aliphatic hydrocarbon radicals.
22. The compound according to claim 17, wherein the radicals
R.sub.1 and R.sub.2 are each identical and/or the radicals R.sub.4,
R.sub.5, R.sub.6 are each identical.
23. A polyurea system comprising as component A)
isocyanate-functional prepolymers obtainable by reaction of
aliphatic polyisocyanates A1) with polyols A2), as component B) the
amino-functional compound according to claim 17, optionally as
component C) organic fillers, which in particular can have a
viscosity at 23.degree. C., measured in accordance with DIN 53019,
in the range of from 10 to 6000 mPas, optionally as component D)
reaction products of isocyanate-functional prepolymers according to
component A) with amino-functional compounds according to component
B) and/or organic fillers according to component C), and optionally
as component E) water and/or a tertiary amine.
24. The polyurea system as claimed in claim 23, wherein said
polyols A2) have a number-average molecular weight of .gtoreq.400
g/mol and an average OH functionality of 2 to 6.
25. The polyurea system according to claim 23, wherein the polyols
A2) comprise polyester polyols and/or polyester-polyether polyols
and/or polyether polyols and/or polyether polyols having an
ethylene oxide content of from 60 to 90 wt. %.
26. The polyurea system according to claim 23, wherein the polyols
A2) comprise polyester-polyether polyols and/or polyether polyols
having an ethylene oxide content of from 60 to 90 wt. %.
27. The polyurea system according to claim 23, wherein the polyols
A2) have a number-average molecular weight of from 4000 to 8500
g/mol.
28. The polyurea system according to claim 23, wherein the
prepolymers A) have a mean NCO functionality of from 1.5 to
2.5.
29. The polyurea system according to claim 23, wherein the
prepolymers A) have a mean NCO functionality of 2.
30. The polyurea system according to claim 23, wherein the organic
fillers of component C) are hydroxy-functional compounds having
repeating ethylene oxide units.
31. The polyurea system according to claim 25, wherein the fillers
of component C) have a mean OH functionality of from 1.5 to 3.
32. The polyurea system according to claim 23 wherein component E)
comprises a tertiary amine of the general formula (II) ##STR00009##
wherein R.sub.7, R.sub.8, R.sub.9 independently of one another can
be alkyl or heteroalkyl radicals having heteroatoms in the alkyl
chain or at the end thereof, or R.sub.7 and R.sub.8 together with
the nitrogen atom carrying them can form an aliphatic, unsaturated
or aromatic heterocycle which can optionally contain further
heteroatoms.
33. The polyurea system according to claim 23, wherein the tertiary
amine is selected from the group consisting of triethanolamine,
tetrakis(2-hydroxyethyl)ethylenediamine,
N,N-dimethyl-2-(4-methylpiperazin-1-yl)ethanamine,
1-{[2-(dimethylamino)ethyl](methyl)amino}ethanol and
3,3',3''-(1,3,5-triazinane-1,3,5-triyl)tris(N,N-dimethyl-propan-1-amine).
34. The polyurea system according to claim 23, wherein component E)
comprises from 0.2 to 2.0 wt. % water and/or from 0.1 to 1.0 wt. %
of the tertiary amine.
35. The polyurea system according to claim 23 for sealing, bonding,
gluing or covering cell tissue, for stopping the escape of blood or
tissue fluids or for sealing leaks in cell tissue.
36. The polyurea system according to claim 30 for use for sealing,
bonding, gluing or covering human or animal cell tissue.
37. A metering system comprising two chambers for the polyurea
system according to claim 21, wherein one chamber contains
component A) and the other chamber contains component B) and
optionally components C), D) and E) of the polyurea system.
Description
[0001] The present invention relates to an amino-functional
compound for use in a polyurea system which is provided in
particular for the sealing, bonding, gluing or covering of cell
tissue. The invention further provides a polyurea system comprising
the compound according to the invention, and a metering system for
the polyurea system according to the invention.
[0002] Various materials which are used as tissue adhesives are
available commercially. They include the cyanoacrylates
Dermabond.RTM. (octyl 2-cyanoacrylate) and Histoacryl Blue.RTM.
(butyl cyanoacrylate). However, a prerequisite for efficient
bonding of cyanoacrylates is a dry substrate. Such adhesives fail
where there is pronounced bleeding.
[0003] As an alternative to the cyanoacrylates, biological
adhesives such as, for example, BioGlue.RTM., a mixture of
glutaraldehyde and bovine serum albumin, various collagen- and
gelatin-based systems (FloSeal.RTM.) and the fibrin adhesives
(Tissucol) are available. Such systems are used primarily for
stopping bleeding (haemostasis). In addition to the high costs,
fibrin adhesives are distinguished by a relatively weak adhesive
strength and rapid degradation, so that they can only be used in
the case of relatively small injuries on unstretched tissue.
Collagen- and gelatin-based systems such as FloSeal.RTM. are used
solely for haemostasis. In addition, because fibrin and thrombin
are obtained from human material and collagen and gelatin are
obtained from animal material, there is always the risk of an
infection in biological systems. Biological materials must
additionally be stored in cool conditions, so that their use in
emergency care, such as, for example, in disaster areas, in
military campaigns, etc., is not possible. Traumatic wounds are
treated in such cases with QuikClot.RTM. or QuikClot ACS+.TM.,
which is a mineral granulate that is introduced into the wound in
an emergency and, by removing water, leads to coagulation. In the
case of QuikClot.RTM., this is a strongly exothermic reaction,
which leads to burns. QuikClot ACS+.TM. is a gauze into which the
salt is embedded. The system must be pressed firmly onto the wound
in order to stop the bleeding.
[0004] The preparation and use of polyurea systems as tissue
adhesives is known from WO 2009/106245 A2. The systems disclosed
therein comprise at least two components. The components are an
amino-functional aspartic acid ester and an isocyanate-functional
prepolymer, which is obtainable by reaction of aliphatic
polyisocyanates with polyester polyols. The described 2-component
polyurea systems can be used as tissue adhesives for sealing wounds
in human and animal cell structures. A very good adhesion result
can thereby be achieved.
[0005] In order to ensure good miscibility of the two components of
the polyurea system, the viscosity of the components at 23.degree.
C. should be less than 10,000 mPas where possible. Prepolymers
having NCO functionalities of less than 3 exhibit such a
correspondingly low viscosity. When such prepolymers are used, it
is necessary to use as the second component an aspartic acid ester
having an amino functionality of more than 2, because it is
otherwise not possible to produce a polymer network. This is
necessary, however, in order that the polyurea system, or a seam
consisting thereof, has the desired mechanical properties such as
elasticity and strength. Moreover, it is a disadvantage when using
difunctional aspartic acid esters that the curing time is up to 24
hours, the polyurea system in many cases remaining tacky, that is
to say is not tack-free, even after that time.
[0006] The object of the invention was, therefore, to provide an
isocyanate-reactive component for a polyurea system, which
isocyanate-reactive component is readily miscible with a prepolymer
having an NCO functionality of less than 3, has an amino
functionality of more than 2 and can be reacted quickly with the
prepolymer to form a three-dimensional polyurea network. An
additional condition to be taken into consideration was that the
cured system does not have cytotoxicity according to ISO 10993 when
used in humans or in animals.
[0007] The object is achieved according to the invention by a
compound of formula (I)
##STR00002##
[0008] wherein [0009] R.sub.1, R.sub.2 each independently of the
other are identical or different organic radicals which do not
contain Zerewitinoff-active hydrogen, and [0010] R.sub.4, R.sub.5,
R.sub.6 each independently of the others are saturated, linear or
branched organic radicals which do not contain Zerewitinoff-active
hydrogen and which are also optionally substituted in the chain by
heteroatoms.
[0011] The compound according to the invention can readily be mixed
with a prepolymer because it has a viscosity of less than 10,000
mPas at 23.degree. C. In addition, it has an amino functionality of
3 and is consequently able quickly to form a three-dimensional
polyurea network with prepolymers having an NCO functionality of 2.
The network is distinguished by high elasticity, strength, adhesive
strength and an absence of cytotoxicity. Moreover, the network is
no longer tacky, that is to say is tack-free, after only a short
time.
[0012] In formula (I), the radicals R.sub.4, R.sub.5, R.sub.6 each
independently of the others can be linear or branched, in
particular saturated, aliphatic C1 to C12, preferably C2 to C10,
particularly preferably C3 to C8 and most particularly preferably
C3 to C6 hydrocarbon radicals. Such amino-functional compounds are
distinguished by the fact that they cure particularly quickly with
prepolymers to form a highly adhesive, elastic and strong polyurea
network.
[0013] According to a further preferred embodiment of the compound
according to the invention, the radicals R.sub.1, R.sub.2 each
independently of the other are linear or branched organic C1 to
C10, preferably C1 to C8, particularly preferably C2 to C6, most
particularly preferably C2 to C4 radicals and in particular are
aliphatic hydrocarbon radicals. This compound too is distinguished
by rapid network formation on reaction with a prepolymer.
[0014] It is likewise preferred for the radicals R.sub.1 and
R.sub.2 each to be identical and/or the radicals R.sub.4, R.sub.5,
R.sub.6 each to be identical.
[0015] Most particular preference is given to a compound of formula
(I) wherein R.sub.1 and R.sub.2 are each simultaneously methyl or
ethyl and R.sub.4, R.sub.5, R.sub.6 are each simultaneously ethyl,
propyl or butyl.
[0016] The invention further provides a polyurea system comprising
[0017] as component A) isocyanate-functional prepolymers obtainable
by reaction of [0018] aliphatic polyisocyanates A1) with [0019]
polyols A2), which in particular can have a number-average
molecular weight of .gtoreq.400 g/mol and a mean OH functionality
of from 2 to 6, [0020] as component B) an amino-functional compound
of formula (I) according to the invention, [0021] optionally as
component C) organic fillers, which in particular can have a
viscosity at 23.degree. C., measured in accordance with DIN 53019,
in the range of from 10 to 6000 mPas, [0022] optionally as
component D) reaction products of isocyanate-functional prepolymers
according to component A) with amino-functional compounds according
to component B) and/or organic fillers according to component C),
and [0023] optionally as component E) water and/or a tertiary
amine.
[0024] The polyurea systems according to the invention are obtained
by mixing the prepolymers A) with the amino-functional compound B)
and optionally components C), D) and/or E). The ratio of free or
blocked amino groups to free NCO groups is preferably 1:1.5,
particularly preferably 1:1. Water and/or amine are thereby added
to component B) or C).
[0025] The isocyanate-functional prepolymers A) are obtainable by
reaction of polyisocyanates A1) with polyols A2), optionally with
the addition of catalysts as well as auxiliary substances and
additives.
[0026] As polyisocyanates A1) there can be used, for example,
monomeric aliphatic or cycloaliphatic di- or tri-isocyanates such
as 1,4-butylene diisocyanate (BDI), 1,6-hexamethylene diisocyanate
(HDI), isophorone diisocyanate (IPDI), 2,2,4- and/or
2,4,4-trimethylhexamethylene diisocyanate, the isomeric
bis-(4,4'-isocyanatocyclohexyl)-methanes or mixtures thereof of any
desired isomer content, 1,4-cyclohexylene diisocyanate,
4-isocyanatomethyl-1,8-octane diisocyanate (nonane triisocyanate),
and alkyl 2,6-diisocyanatohexanoate (lysine diisocyanate) having
C1-C8-alkyl groups.
[0027] In addition to the monomeric polyisocyanates A1) mentioned
above there can also be used the higher molecular weight secondary
products thereof having a uretdione, isocyanurate, urethane,
allophanate, biuret, iminooxadiazinedione or oxadiazinetrione
structure and mixtures thereof.
[0028] Preference is given to the use of polyisocyanates A1) of the
above-mentioned type having only aliphatically or
cycloaliphatically bonded isocyanate groups or mixtures
thereof.
[0029] It is likewise preferred for polyisocyanates A1) of the
above-mentioned type having a mean NCO functionality of from 1.5 to
2.5, preferably of from 1.6 to 2.4, more preferably of from 1.7 to
2.3, most particularly preferably of from 1.8 to 2.2 and in
particular of 2 to be used.
[0030] Hexamethylene diisocyanate is most particularly preferably
used as the polyisocyanate A1).
[0031] According to a preferred embodiment of the polyurea system
according to the invention, it is provided that the polyols A2) are
polyester polyols and/or polyester-polyether polyols and/or
polyether polyols. Particular preference is given to
polyester-polyether polyols and/or polyether polyols having an
ethylene oxide content of from 60 to 90 wt. %.
[0032] It is also preferred for the polyols A2) to have a
number-average molecular weight of from 4000 to 8500 g/mol.
[0033] Suitable polyether ester polyols are prepared according to
the prior art preferably by polycondensation from polycarboxylic
acids, anhydrides of polycarboxylic acids and esters of
polycarboxylic acids with readily volatile alcohols, preferably C1
to C6 monools, such as methanol, ethanol, propanol or butanol, with
low molecular weight and/or higher molecular weight polyol in molar
excess; wherein there are used as the polyol ether-group-containing
polyols optionally in mixtures with other ether-group-free
polyols.
[0034] Mixtures of the higher molecular weight and of the low
molecular weight polyols can, of course, also be used for the
polyether ester synthesis.
[0035] Such low molecular weight polyols in molar excess are
polyols having molar masses of from 62 to 299 daltons, having from
2 to 12 carbon atoms and hydroxyl functionalities of at least 2,
which can further be branched or unbranched and the hydroxyl groups
of which are primary or secondary. These low molecular weight
polyols can also contain ether groups. Typical representatives are
ethylene glycol, 1,2-propanediol, 1,3-propanediol, 1,4-butanediol,
2,3-butanediol, 2-methyl-1,3-propanediol, 1,5-pentanediol,
1,6-hexanediol, 3-methyl-1,5-pentanediol, 1,8-octanediol,
1,10-decanediol, 1,12-dodecanediol, cyclohexanediol, diethylene
glycol, triethylene glycol and higher homologues, dipropylene
glycol, tripropylene glycol and higher homologues, glycerol,
1,1,1-trimethylolpropane, and oligo-tetrahydrofurans with hydroxyl
end groups. Mixtures within this group can, of course, also be
used.
[0036] Higher molecular weight polyols in molar excess are polyols
having molar masses of from 300 to 3000 daltons, which can be
obtained by ring-opening polymerisation of epoxides, preferably
ethylene oxide and/or propylene oxide, as well as by
acid-catalysed, ring-opening polymerisation of tetrahydrofuran.
Either alkali hydroxides or double-metal-cyanide catalysts can be
used for the ring-opening polymerisation of epoxides.
[0037] As starters for ring-opening epoxide polymerisations there
can be used all at least bifunctional molecules from the group of
the amines and the above-mentioned low molecular weight polyols.
Typical representatives are 1,1,1-trimethylolpropane, glycerol,
o-TDA, ethylenediamine, 1,2-propylene glycol, etc., as well as
water, including mixtures thereof. Mixtures within the group of the
excess higher molecular weight polyols can, of course, also be
used.
[0038] The synthesis of the higher molecular weight polyols, in so
far as hydroxyl-group-terminated polyalkylene oxides of ethylene
oxide and/or propylene oxide are concerned, can be effected
randomly or block-wise, it also being possible for mixed blocks to
be present.
[0039] Polycarboxylic acids are both aliphatic and aromatic
carboxylic acids, which can be both cyclic, linear, branched or
unbranched and which can contain from 4 to 24 carbon atoms.
[0040] Examples are succinic acid, glutaric acid, adipic acid,
azelaic acid, sebacic acid, 1,10-decanedicarboxylic acid,
1,12-dodecanedicarboxylic acid, phthalic acid, terephthalic acid,
isophthalic acid, trimellitic acid, pyromellitic acid. Succinic
acid, glutaric acid, adipic acid, sebacic acid, lactic acid,
phthalic acid, terephthalic acid, isophthalic acid, trimellitic
acid, pyromellitic acid are preferred. Succinic acid, glutaric acid
and adipic acid are particularly preferred.
[0041] The group of the polycarboxylic acids also includes
hydroxycarboxylic acids, or their inner anhydrides, such as, for
example, caprolactone, lactic acid, hydroxybutyric acid, ricinoleic
acid, etc. Also included are monocarboxylic acids, in particular
those which have more than 10 carbon atoms, such as soybean oil
fatty acid, palm oil fatty acid and groundnut oil fatty acid,
wherein the proportion thereof in the whole of the reaction mixture
constituting the polyether ester polyol is not more than 10 wt. %
and, in addition, the accompanying low functionality is compensated
for by the concomitant use of at least trifunctional polyols,
whether it be on the side of the low molecular weight or high
molecular weight polyols.
[0042] According to the prior art, the preparation of the polyether
ester polyol is carried out at elevated temperature in the range
from 120 to 250.degree. C., initially under normal pressure, later
with the application of a vacuum of from 1 to 100 mbar, preferably,
but not necessarily, using an esterification or transesterification
catalyst, the reaction being completed until the acid number falls
to values of from 0.05 to 10 mg KOH/g, preferably from 0.1 to 3 mg
KOH/g and particularly preferably from 0.15 to 2.5 mg KOH/g.
[0043] An inert gas can further be used during the normal pressure
phase prior to the application of a vacuum. Of course, liquid or
gaseous entrainers can also be used as an alternative or for
individual phases of the esterification. For example, the water of
reaction can be discharged equally as well when nitrogen is used as
carrier gas as when an azeotropic entrainer, such as, for example,
benzene, toluene, xylene, dioxane, etc., is used.
[0044] Mixtures of polyether polyols with polyester polyols in
arbitrary ratios can, of course, also be used.
[0045] Polyether polyols are preferably polyalkylene oxide
polyethers based on ethylene oxide and optionally propylene
oxide.
[0046] Such polyether polyols are preferably based on difunctional
or higher functional starter molecules such as difunctional or
higher functional alcohols or amines.
[0047] Examples of such starters are water (regarded as a diol),
ethylene glycol, propylene glycol, butylene glycol, glycerol, TMP,
sorbitol, pentaerythritol, triethanolamine, ammonia or
ethylenediamine.
[0048] Hydroxyl-group-containing polycarbonates, preferably
polycarbonate diols, having number-average molecular weights
M.sub.n of from 400 to 8000 g/mol, preferably from 600 to 3000
g/mol, can likewise be used. They are obtainable by reaction of
carbonic acid derivatives, such as diphenyl carbonate, dimethyl
carbonate or phosgene, with polyols, preferably diols.
[0049] Examples of such diols are ethylene glycol, 1,2- and
1,3-propanediol, 1,3- and 1,4-butanediol, 1,6-hexanediol,
1,8-octanediol, neopentyl glycol, 1,4-bishydroxymethylcyclohexane,
2-methyl-1,3-propanediol, 2,2,4-trimethyl-1,3-pentanediol,
dipropylene glycol, polypropylene glycols, dibutylene glycol,
polybutylene glycols, bisphenol A and lactone-modified diols of the
above-mentioned type.
[0050] For the preparation of the prepolymer A), the polyisocyanate
A1) can be reacted with the polyol A2) with an NCO/OH ratio of
preferably from 4:1 to 12:1, particularly preferably 8:1, and then
the content of unreacted polyisocyanate can be separated off by
suitable methods. Thin-film distillation is conventionally used for
that purpose, prepolymers having residual monomer contents of less
than 1 wt. %, preferably less than 0.1 wt. %, most particularly
preferably less than 0.03 wt. %, being obtained.
[0051] During the preparation, stabilisers such as benzoyl
chloride, isophthaloyl chloride, dibutyl phosphate,
3-chloropropionic acid or methyl tosylate can optionally be
added.
[0052] The reaction temperature in the preparation of the
prepolymers A) is preferably from 20 to 120.degree. C. and more
preferably from 60 to 100.degree. C.
[0053] The prepolymers that are prepared have a mean NCO content,
measured in accordance with DIN EN ISO 11909, of from 2 to 10 wt.
%, preferably from 2.5 to 8 wt. %.
[0054] According to a further embodiment of the polyurea system
according to the invention, the prepolymers A) can have a mean NCO
functionality of from 1.5 to 2.5, preferably of from 1.6 to 2.4,
more preferably of from 1.7 to 2.3, most particularly preferably of
from 1.8 to 2.2 and in particular of 2.
[0055] The organic fillers of component C) can preferably be
hydroxy-functional compounds, in particular polyether polyols
having repeating ethylene oxide units.
[0056] It is also advantageous for the fillers of component C) to
have a mean OH functionality of from 1.5 to 3, preferably of from
1.8 to 2.2 and particularly preferably of 2.
[0057] For example, there can be used as organic fillers
polyethylene glycols that are liquid at 23.degree. C., such as PEG
200 to PEG 600, their mono- or di-alkyl ethers such as PEG 500
dimethyl ether, liquid polyether and polyester polyols, liquid
polyesters such as, for example, Ultramoll (Lanxess AG, Leverkusen,
DE), and glycerol and its liquid derivatives such as, for example,
triacetin (Lanxess AG, Leverkusen, DE).
[0058] The viscosity of the organic fillers, measured in accordance
with DIN 53019 at 23.degree. C., is preferably from 50 to 4000
mPas, particularly preferably from 50 to 2000 mPas.
[0059] In a preferred embodiment of the polyurea system according
to the invention, polyethylene glycols are used as organic fillers.
They preferably have a number-average molecular weight of from 100
to 1000 g/mol, particularly preferably from 200 to 400 g/mol.
[0060] In order further to reduce the mean equivalent weight of the
compounds used overall for the prepolymer crosslinking, based on
the NCO-reactive groups, it is additionally possible to prepare
reaction products of the prepolymers A) with the amino-functional
compound B) and/or the organic fillers C), provided they are amino-
or hydroxy-functional, in a separate preliminary reaction and then
use them as the higher molecular weight curing agent component.
[0061] Preferably, ratios of isocyanate-reactive groups to
isocyanate groups of from 50 to 1 to 1.5 to 1, particularly
preferably from 15 to 1 to 4 to 1, are established in the
pre-extension.
[0062] The advantage of this modification by pre-extension is that
the equivalent weight and the equivalent volume of the curing agent
component can be modified within wider limits. Commercially
available 2-chamber metering systems can accordingly be used for
the application, in order to obtain an adhesive system which, with
existing chamber volume ratios, can be adjusted to the desired
ratio of NCO-reactive groups to NCO groups.
[0063] According to a further embodiment of the polyurea system
according to the invention, it is provided that component E)
comprises a tertiary amine of the general formula (II)
##STR00003##
[0064] wherein
[0065] R.sub.7, R.sub.8, R.sub.9 independently of one another can
be alkyl or heteroalkyl radicals having heteroatoms in the alkyl
chain or at the end thereof, or R.sub.7 and R.sub.8 together with
the nitrogen atom carrying them can form an aliphatic, unsaturated
or aromatic heterocycle which can optionally contain further
heteroatoms.
[0066] These polyurea systems are distinguished by particularly
rapid curing.
[0067] The compounds used in component E) can most particularly
preferably be tertiary amine selected from the group
triethanolamine, tetrakis(2-hydroxyethyl)ethylenediamine,
N,N-dimethyl-2-(4-methylpiperazin-1-yl)ethanamine,
2-{[2-(dimethylamino)ethyl](methyl)amino}-ethanol,
3,3',3''-(1,3,5-triazinane-1,3,5-triyl)tris(N,N-dimethyl-propan-1-amine).
[0068] Very particularly high curing speeds can also be achieved if
component E) comprises from 0.2 to 2.0 wt. % water and/or from 0.1
to 1.0 wt. % of the tertiary amine.
[0069] It is, of course, also possible to incorporate into the
polyurea systems pharmacologically active ingredients such as
analgesics with and without anti-inflammatory activity,
antiphlogistics, substances having antimicrobial activity,
antimycotics, substances having antiparasitic activity.
[0070] The polyurea system according to the invention is suitable
in particular for sealing, bonding, gluing or covering cell tissue
and in particular for stopping the escape of blood or tissue fluids
or for sealing leaks in cell tissue. Most particularly preferably,
it can be used for the production of an agent for sealing, bonding,
gluing or covering human or animal cell tissue. By means of the
polyurea system according to the invention it is possible to
produce rapidly curing, transparent, flexible and biocompatible
seams which adhere firmly to the tissue.
[0071] The invention further provides a metering system having two
chambers for a polyurea system according to the invention, in which
one chamber contains component A) and the other chamber contains
component B) and optionally components C), D) and E) of the
polyurea system. Such a metering system is suitable in particular
for applying the polyurea system as an adhesive to tissue.
EXAMPLES
[0072] The invention is explained in greater detail below by means
of examples.
Methods
[0073] Molecular weight: The molecular weights were determined by
means of gel permeation chromatography (GPC) as follows:
Calibration is carried out using polystyrene standards with
molecular weights of Mp 1,000,000 to 162. Tetrahydrofuran p.A. was
used as eluant. The following parameters were observed during the
double measurement: degassing: online degasser; flow rate: 1
ml/min; analysis time: 45 minutes; detectors: refractometer and UV
detector; injection volume: 100 .mu.l-200 .mu.l. Calculation of the
molar mass means M.sub.w; M.sub.n and M.sub.p and of the
polydispersity M.sub.w/M.sub.n was carried out with software
assistance. Baseline points and evaluation limits were fixed in
accordance with DIN 55672 Part 1.
[0074] NCO content: Unless expressly mentioned otherwise, the NCO
content was determined volumetrically in accordance with DIN-EN ISO
11909.
[0075] Viscosity: The viscosity was determined in accordance with
ISO 3219 at 23.degree. C.
[0076] Residual monomer content: The residual monomer content was
determined in accordance with DIN ISO 17025.
[0077] NMR: The NMR spectra were recorded using a Bruker DRX 700
device.
Substances
[0078] Polyethylene glycol 600 (Aldrich)
Synthesis of tetraethyl
2,2'-(4-(3-(1,4-diethoxy-1,4-dioxobutan-2-ylamino)propyl)heptane-1,7-diyl-
)bis(azandiyl)disuccinate (3)
4-(2-Cyanoethyl)heptanedinitrile (1)
##STR00004##
[0080] A mixture of 12.2 g (55.4 mmol) of
4-(2-cyanoethyl)-4-nitroheptanedinitrile and 18 ml of tributyltin
dihydride was heated at reflux overnight with 2.78 g of
azo-bis-(isobutyronitrile) (AIBN) in 250 ml of acetonitrile. After
removal of the solvent in vacuo, the product was stirred with
n-hexane and crystallised with a mixture of n-hexane and
dichloromethane. 8.25 g (85%) of the product were obtained in the
form of a colourless solid.
4-(3-Aminopropyl)heptane-1,7-diamine (2)
##STR00005##
[0082] 8 g (45 7 mmol) of 4-(2-cyanoethyl)heptanedinitrile were
hydrogenated for 5 hours at 130.degree. C. and a hydrogen pressure
of 100 bar in 100 ml of 7N methanolic ammonia solution. After
cooling to room temperature, the reaction mixture was filtered over
kieselguhr and washed with methanol. After removal of the solvent
in vacuo, 7.5 g of the crude product were obtained and were used in
the next stage without being purified further.
Tetraethyl
2,2'-(4-(3-(1,4-diethoxy-1,4-dioxobutan-2-ylamino)propyl)heptan-
e-1,7-diyl)bis-(azandiyl)disuccinate (3)
##STR00006##
[0084] 25.7 g (150 mmol) of maleic acid diethyl ester were added to
a solution of 7.5 g (40 mmol) of
4-(3-aminopropyl)heptane-1,7-diamine in 100 ml of ethanol. The
reaction mixture was stirred for 3 days at 60.degree. C. After
removal of the solvent in vacuo, the product was purified by column
chromatography (hexane/ethyl acetate 1:1, then
dichloromethane/methanol 10:1). 15.5 g (39%) of the product were
obtained in the form of a yellow oil.
[0085] .sup.1H-NMR (CDCl.sub.3, 700 MHz): .delta.=1.27 (t, 9H),
1.28 (m, 6H), 1.29 (t, 9H), 1.42 (m, 6H) 1.72 (s, 3NH), 2.48 (m,
1H), 2.61, (m, 6H), 2.64 (dd, 6H), 3.60 (t, 3H), 4.19 (q, 6H), 4.2
(q, 6H).
[0086] .sup.13C-NMR (CDCl.sub.3, 700 MHz): 13.93, 13.99, 26.9,
30.6, 36.9, 37.9, 48.3, 57.6, 60.4, 60.9, 170.6, 173.4.
Synthesis of Prepolymer A
[0087] 212.5 g (1.8 mol) of succinic acid were heated to
235.degree. C., with stirring, with 1591.5 g of polyethylene glycol
600 (2.6 mol). The water that formed was distilled off for a period
of 8.5 hours. 100 ppm of tin(II) chloride were then added, and
heating at 235.degree. C. was continued for a further 9 hours in
vacuo (15 mbar) in a water separator.
[0088] 672 g of HDI (4 mol) were placed in a reaction vessel with
0.1 wt. % benzoyl chloride and heated to 80.degree. C. 788 g of the
polyester were then metered in, with stirring, over a period of one
hour, and stirring was continued at 80.degree. C. until a constant
NCO content was reached. Excess HDI was removed at 140.degree. C.
and 0.13 mbar by means of a thin-film evaporator. The resulting
prepolymer had an NCO content of 3.5% and a viscosity of 4700
mPas/23.degree. C. The residual monomer content was <0.03%
HDI.
Synthesis of Prepolymer B
[0089] A prepolymer was prepared analogously to prepolymer A from
263 g (1.8 mol) of adipic acid and 1591.5 g of polyethylene glycol
600 (2.6 mol). The resulting prepolymer had an NCO content of 5.93%
and a viscosity of 1450 mPas/23.degree. C. The residual monomer
content was <0.03% HDI.
Synthesis of Prepolymer C
[0090] 465 g of HDI and 2.35 g of benzoyl chloride were placed in a
one-litre four-necked flask. Within a period of 2 hours, 931.8 g of
a polyether having an ethylene oxide content of 71% and a propylene
oxide content of 29% (in each case based on the total alkylene
oxide content) were added at 80.degree. C., and stirring was then
carried out for one hour. Excess HDI was then distilled off by
thin-film distillation at 130.degree. C. and 0.13 mbar. 980 g (71%)
of a prepolymer having an NCO content of 2.37% and a viscosity of
4500 mPas/23.degree. C. were obtained. The residual monomer content
was <0.03% HDI.
Production of the Tissue Adhesive
[0091] 4 g of the prepolymer in question were stirred thoroughly in
a beaker with an equivalent amount of the amino-functional compound
3 which had been prepared Immediately thereafter, the polyurea
system was applied as a thin layer to the muscle tissue to be
bonded. The time for which the polyurea system had a sufficiently
low viscosity that it could be applied to the tissue without
difficulty was determined as the processing time.
[0092] The time after which the polyurea system was no longer tacky
(tack free time) was measured by adhesion tests using a glass rod.
To that end, the glass rod was brought into contact with the layer
of the polyurea system. When the rod no longer adhered, the system
was considered to be tack-free. In addition, the adhesive force was
determined by coating two pieces of muscle tissue (1=4 cm, h=0.3
cm, b=1 cm) with the polyurea system 1 cm from the ends and
adhesively bonding them so that they overlapped. The adhesive force
of the polyurea system was tested in each case by pulling.
TABLE-US-00001 Curing Adhesive agent Processing time Tack free time
force Prepolymer A 3 1 min 30 s 2 min ++ Prepolymer B 3 1 min 2 min
+ Prepolymer B 4 8 min >30 min + (Comparison Example 1)
Prepolymer A 5 3 min 5 min ++ ++: very good; +: good
Comparison Example 1: Difunctional Prepolymer+Difunctional Curing
Agent
[0093] Instead of the amino-functional compound 3 which had been
prepared, tetraethyl
2,2'-[(2-methylpentane-1,5-diyl)diimino]dibutanoate (4) described
in EP 2 145 634 was reacted with prepolymer B. The processing time
here was 8 minutes. The polyurea system was still not tack-free
even after 10 minutes.
Measurement of the Cytotoxicity of an Adhesive Produced with
(3)
[0094] Prepolymer C was reacted with an equivalent amount of 3. The
cytotoxicity was measured in accordance with ISO 10993-5:2009 using
L929 cells. There was no reduction in cell viability. Accordingly,
the polyurea system is not to be categorised as cytotoxic.
Comparison Example 2: Cytotoxicity of a Structurally Similar
Trifunctional Curing Agent
[0095] Diethyl
2-[(8-[(1,4-diethoxy-1,4-dioxobutan-2-yl)amino]-4-{[(1,4-diethoxy-1,4-dio-
xobutan-2-yl)-amino]methyl}octyl)amino]butanedioate (5)
##STR00007##
[0096] 346 g (2 mol) of maleic acid diethyl ester were added
dropwise to 115.3 g (0.6 mol) of triaminononane. The reaction
mixture was heated at 60.degree. C. for 3 days until no further
maleic acid ester was detectable (Bayer reagent).
Measurement of the Cytotoxicity of the Cured Adhesive
[0097] 4 g of prepolymer C were stirred thoroughly in a beaker with
an equivalent amount of (5) and cured. The adhesive was measured in
accordance with ISO 10993-5:2009 using L929 cells. The cell
viability fell to 4% (high cyctotoxicity).
* * * * *